A clinical therapeutic protein drug-drug interaction study: coadministration of denosumab and midazolam in postmenopausal women with osteoporosis

Graham Jang, Allegra Kaufman, Edward Lee, Lisa Hamilton, Shauna Hutton, Ogo Egbuna, Desmond Padhi, Graham Jang, Allegra Kaufman, Edward Lee, Lisa Hamilton, Shauna Hutton, Ogo Egbuna, Desmond Padhi

Abstract

Drug-disease interactions involving therapeutic proteins that target cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to drug regulatory agencies and industry sponsors in recent years. This parallel-group open-label study evaluated the effects of the monoclonal antibody denosumab, an inhibitor of the cytokine RANKL, on the pharmacokinetics of the probe CYP3A4 substrate midazolam in postmenopausal women with osteoporosis. The pharmacokinetics of a 2 mg oral dose of midazolam was evaluated on days 1 and 16. Subjects in Group A received a 60 mg subcutaneous dose of denosumab on day 2, 2 weeks before the second midazolam dose, while subjects in Group B did not. For Group A (n = 17), point estimates for the ratio of least square means for midazolam exposures based on maximum observed plasma concentration (C max) and areas under the plasma concentration-time curve (AUCs) on day 16 versus day 1 ranged from 1.02 to 1.04 and 90% confidence intervals were within 0.80-1.25. No period effect was observed for Group B (n = 8). Midazolam and denosumab coadministration was safe and well tolerated. Inhibition of the cytokine RANKL by denosumab does not affect CYP3A4 in postmenopausal women with osteoporosis and will not alter the pharmacokinetics of drugs metabolized by this enzyme. These results are consistent with data suggesting that RANKL does not impact markers of inflammation and represent the first clinical data demonstrating a lack of effect on CYP3A4 of a therapeutic protein that is a cytokine modulator.

Keywords: CYP; cytochrome P450; cytokine modulator; denosumab; drug–drug interaction; menopause; midazolam; postmenopausal; therapeutic protein.

Figures

Figure 1
Figure 1
Study design and treatment schema. PK, pharmacokinetics; SC, subcutaneous.
Figure 2
Figure 2
Mean (SD) Plasma midazolam concentration–time profiles following two midazolam oral doses (2 mg) in the absence (day 1) and presence (day 16) of denosumab in postmenopausal women (Group A; n = 17*). * Of the 18 subjects who completed study treatment in Group A, 17 were included in pharmacokinetics parameter estimates and 1 was excluded because of prohibited medication use (diltiazem; see text).
Figure 3
Figure 3
Individual (Circles) and mean (Squares) Cmax and AUC0-inf ratios for midazolam in Groups A (midazolam + denosumab) and B (midazolam alone).

References

    1. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, et al. Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol. 1993;44:707–715.
    1. Aitken AE, Morgan ET. Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab Dispos. 2007;35:1687–1693.
    1. Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol. 2006;46:123–149.
    1. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390:175–179.
    1. Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059–1066.
    1. Bone HG, Bolognese MA, Yuen CK, Kendler DL, Wang H, Liu Y, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab. 2008;93:2149–2157.
    1. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009;24:153–161.
    1. Chaudhary RS, Gangwal SS, Avachat MK, Shah YN, Jindal KC. Determination of diltiazem hydrochloride in human serum by high-performance liquid chromatography. J Chromatogr. 1993;614:261–266.
    1. Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 2008;58:1299–1309.
    1. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–765.
    1. Dickmann LJ, Patel SK, Rock DA, Wienkers LC, Slatter JG. Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos. 2011;39:1415–1422.
    1. Dickmann LJ, Patel SK, Wienkers LC, Slatter JG. Effects of interleukin 1β (IL-1β) and IL-1β/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Curr Drug Metab. 2012;13:930–937.
    1. Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung MR, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011;26:530–537.
    1. Eklund CM. Proinflammatory cytokines in CRP baseline regulation. Adv Clin Chem. 2009;48:111–136.
    1. Evers R, Dallas S, Dickmann LJ, Fahmi OA, Kenny JR, Kraynov E, et al. Critical review of preclinical approaches to investigate Cytochrome P450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: a white paper. Drug Metab Dispos. 2013;41:1598–1609.
    1. Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012;64:617–629.
    1. Food and Drug Administration. Draft Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. Rockville, MD: US Department of Health and Human Services; 2012. Available at (accessed 20 February 2012)
    1. Girish S, Martin SW, Peterson MC, Zhang LK, Zhao H, Balthasar J, et al. AAPS workshop report: strategies to address therapeutic protein-drug interactions during clinical development. AAPS J. 2011;13:405–416.
    1. Gorski JC, Vannaprasaht S, Hamman MA, Ambrosius WT, Bruce MA, Haehner-Daniels B, et al. The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity. Clin Pharmacol Ther. 2003;74:275–287.
    1. Greenblatt DJ, Harmatz JS, von Moltke LL, Wright CE, Shader RI. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clin Pharmacol Ther. 2004;76:467–479.
    1. Gupta P, Alvey C, Wang R, Dowty ME, Fahmi OA, Walsky RL, et al. Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data. Br J Clin Pharmacol. 2012;74:109–115.
    1. Harris RZ, Tsunoda SM, Mroczkowski P, Wong H, Benet LZ. The effects of menopause and hormone replacement therapies on prednisolone and erythromycin pharmacokinetics. Clin Pharmacol Ther. 1996;59:429–435.
    1. Huang SM, Zhao H, Lee JI, Reynolds K, Zhang L, Temple R, et al. Therapeutic protein-drug interactions and implications for drug development. Clin Pharmacol Ther. 2010;87:497–503.
    1. Kenny JR, Liu MM, Chow AT, Earp JC, Evers R, Slatter JG, et al. Therapeutic protein drug-drug interactions: navigating the knowledge gaps-highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop. AAPS J. 2013;15:933–940.
    1. Kraynov E, Martin SW, Hurst S, Fahmi OA, Dowty M, Cronenberger C, et al. How current understanding of clearance mechanisms and pharmacodynamics of therapeutic proteins can be applied for evaluation of their drug-drug interaction potential. Drug Metab Dispos. 2011;39:1779–1783.
    1. Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012;64:970–981.
    1. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165–176.
    1. Lee JI, Zhang L, Men AY, Kenna LA, Huang SM. CYP-mediated therapeutic protein-drug interactions: clinical findings, proposed mechanisms and regulatory implications. Clin Pharmacokinet. 2010;49:295–310.
    1. Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007;22:1832–1841.
    1. Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol. 2004;58:56–60.
    1. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821–831.
    1. Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43:222–229.
    1. Miller PD, Wagman RB, Peacock M, Lewiecki EM, Bolognese MA, Weinstein RL, et al. Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J Clin Endocrinol Metab. 2011;96:394–402.
    1. Morgan ET. Regulation of cytochrome p450 by inflammatory mediators: why and how? Drug Metab Dispos. 2001;29:207–212.
    1. Morgan ET. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009;85:434–438.
    1. Morgan ET, Li-Masters T, Cheng PY. Mechanisms of cytochrome P450 regulation by inflammatory mediators. Toxicology. 2002;181–182:207–210.
    1. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther. 2000;67:267–274.
    1. Özmen B, Kirmaz C, Aydin K, Kafesciler SO, Guclu F, Hekimsoy Z. Influence of the selective oestrogen receptor modulator (raloxifene hydrochloride) on IL-6, TNF-alpha, TGF-beta1 and bone turnover markers in the treatment of postmenopausal osteoporosis. Eur Cytokine Netw. 2007;18:148–153.
    1. Padhi D, Salfi M, Emery M. Cinacalcet does not affect the activity of cytochrome P450 3A enzymes, a metabolic pathway for common immunosuppressive agents: a randomized, open-label, crossover, single-centre study in healthy volunteers. Drugs R D. 2008;9:335–343.
    1. Parmentier JH, Schohn H, Bronner M, Ferrari L, Batt AM, Dauca M, et al. Regulation of CYP4A1 and peroxisome proliferator-activated receptor alpha expression by interleukin-1beta, interleukin-6, and dexamethasone in cultured fetal rat hepatocytes. Biochem Pharmacol. 1997;54:889–898.
    1. Prolia. Denosumab injection for subcutaneous use. Thousand Oaks, CA: Amgen Inc; 2012. Full prescribing information.
    1. Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther. 2011;89:735–740.
    1. Slatter JG, Wienkers LC, Dickmann LJ. Drug interactions of cytokines and anti-cytokine therapeutic proteins. In: Zhou H, Meibohm B, editors. Drug-drug interactions for therapeutic biologics. Hoboken, NJ: John Wiley & Sons Inc; 2013. pp. 215–237.
    1. Stolina M, Dwyer D, Ominsky MS, Corbin T, Van G, Bolon B, et al. Continuous RANKL inhibition in osteoprotegerin transgenic mice and rats suppresses bone resorption without impairing lymphorganogenesis or functional immune responses. J Immunol. 2007;179:7497–7505.
    1. Stolina M, Schett G, Dwyer D, Vonderfecht S, Middleton S, Duryea D, et al. RANKL inhibition by osteoprotegerin prevents bone loss without affecting local or systemic inflammation parameters in two rat arthritis models: comparison with anti-TNFalpha or anti-IL-1 therapies. Arthritis Res Ther. 2009;11:R187.
    1. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA. 2004;101:6062–6067.
    1. Sutjandra L, Rodriguez RD, Doshi S, Ma M, Peterson MC, Jang GR, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793–807.
    1. Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 2011;63:1150–1158.
    1. Tato CM, Cua DJ. SnapShot: Cytokines I. Cell. 2008a;132:324.
    1. Tato CM, Cua DJ. SnapShot: Cytokines II. Cell. 2008b;132:500.
    1. Tato CM, Cua DJ. SnapShot: Cytokines III. Cell. 2008c;132:900.
    1. Tato CM, Cua DJ. SnapShot: Cytokines IV. Cell. 2008d;132:1062.
    1. Winter H, Egizi E, Erondu N, Ginsberg A, Rouse DJ, Severynse-Stevens D, et al. Evaluation of pharmacokinetic interaction between PA-824 and midazolam in healthy adult subjects. Antimicrob Agents Chemother. 2013;57:3699–3703.
    1. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997;272:25190–25194.
    1. XGEVA. Denosumab injection for subcutaneous use. Thousand Oaks, CA: Amgen Inc; 2013. Full prescribing information.
    1. Zhang X, Quinney SK, Gorski JC, Jones DR, Hall SD. Semiphysiologically based pharmacokinetic models for the inhibition of midazolam clearance by diltiazem and its major metabolite. Drug Metab Dispos. 2009;37:1587–1597.
    1. Zhou H, Davis HM. Risk-based strategy for the assessment of pharmacokinetic drug-drug interactions for therapeutic monoclonal antibodies. Drug Discovery Today. 2009;14:891–898.
    1. ZOCOR. Simvastatin tablets. Whitehouse Statin, NJ: Merck & Co., Inc; 2012. Full prescribing information.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera